Rituximab is a chimeric monoclonal antibody that specifically recognizes a CD20 antigen specifically expressed in B-cell lymphocytes (Non-patent Documents 1 and 2). A CD20 antigen is widely expressed on B-cell malignant tumors, typically including such as follicular malignant lymphoma that develops relatively slow and diffuse malignant lymphoma that develops aggressively. Rituximab has been administered as a molecular targeting drug against a CD20 antigen in addition to chemotherapy for these B-cell malignancies expressing the CD20 antigen (Non-patent document 3 to 8). Although the CHOP chemotherapy has been utilized for B-cell lymphoma patients for more than 25 years, unfortunately, the cure rate of diseases has not been improved, even with a combination with other chemotherapies or change of a dosage. However, in recent reports, it has been confirmed that the cure and disease-free survival rates of the diseases are improved significantly by using rituximab for CD20 positive B-cell malignant lymphoma in combination with conventional chemotherapies based on CHOP (Non-patent Documents 3 to 8).
Although 5 years have passed since rituximab was started to be clinically used, the cure rate for CD20 positive malignant lymphomas is still unsatisfactory, and the considerable number of patients treated with rituximab have undergone the progression and transformation of a tumor that is unreative to rituximab (Non-patent Document 9 to 12). Recently, Terui et al reported that 5 out of 48 CD20 positive lymphoma patients showed rituximab resistance and genetic mutations in the CD20-coding sequence region in 10 out of 48 patients were confirmed (Non-patent document 10). A conformational change in the CD20 protein caused by genetic mutations has been speculated to contribute to one of mechanisms of rituximab resistance. However, the relationship between genetic mutations in the CD20-coding sequence region and rituximab resistance is not clearly indicated, which also suggested existence of mechanisms of rituximab resistance other than genetic mutations.
Recently, we had a patient of CD20 positive malignant B-cell lymphoma (diagnosis in onset) transformed to a tumor having a feature of rituximab resistance after repeated administration of rituximab. Disease progression of this patient worsened during the rituximab administration and CD20 expression in lymphoma cells was not observed in pathological findings and studies by flow cytometry (FCM) at the point. Non-patent Document 1: Cheson B D. Monoclocal antibody therapy for B-cell malignancies. Semin Oncol. April 2006; 33(2 Suppl 5): S2-14.    Non-patent Document 2: Imai K, Takaoka A. Comparing antibody and small-molecule therapies for dancer. Nat Rev Cancer. September 2006; 6(9): 714-727.    Non-patent Document 3: Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. Jan. 24, 2003; 346(4): 235-242.    Non-patent Document 4: van Oers M H, Klasa R, Marcus R E, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin's lymphoma, both in patients with and without rituximab during induction: results of a prospective randomized phase III intergroup trial. Blood. Jul. 27, 2006.    Non-patent Document 5: Habermann T M, Weller E A, Morrison V A, et al. Rotuximab-CHOP versus CHOP alone or with maintenance rituximab in order patients with diffuse large B-cell lymphoma. J Clin Oncol. Jul. 1, 2006; 24(19): 3121-3127.    Non-patent Document 6: Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. May 2006; 7(5): 379-391.    Non-patent Document 7: Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. Dec. 1, 2005; 106(12): 3725-3732.    Non-patent Document 8: Czuczman M S, Weaver R, Alkuzweny B, Berlfein J, Grillo-Lopez A J. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. Dec. 1, 2004; 22(23): 4711-4716.    Non-patent Document 9: Alvaro-Naranjo T, Jean-Martinez J, Guma-Padro J, Bosch-Princep R, Salvado-Usach M T. CD20-negative DLBCL transformation after rituximab treatment in follicular lymphoma: a new case report and review of the literature. Ann Hematol. September 2003; 2003; 82(9): 585-588.    Non-patent Document 10: Yasuhito Terui T S, Yuji Mishima, Yuko Mishima, Natsuhiko Sugimura, Kiyotsugu Kojima, Masahiro Yokoyama, Kiyohiko Hatake. Identification of CD20 Mutations in Malignant Lymphoma: Can They Be Predictors of Response to Rituximab? Paper presented at: 47th American Society Of Hematology Annual Meeting; Dec. 12, 2005, 2005; Atlanta.    Non-patent Document 11: Davis T A, Czerwinski D K, Levy R. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin Cancer Res. March 1999; 5(3): 611-615.    Non-patent Document 12: Kinoshita T, Nagai H, Murate T, Saito H. CD20-negative relapse in B-cell lymphoma after treatment with Rituximab. J Clin Oncol. December 1998; 16(12): 3916.    Non-patent Document 13: Crescenzi M, Seto M, Herzig G P, Weiss PD, Griffith R C, Korsmeyer S J. Thermostable DNA polymerase chain amplification of t(14;18) chromosome breakpoints and detection of minimal residual disease. Proc Natl Acad Sci USA. 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